Alzheimer disease is characterized by distinct neuropathological lesions, including intracellular neurofibrillary tangles, extracellular parenchymal and cerebrovascular amyloid deposits, and selective cell death that particularly affects cholinergic neurons in the basal forebrain. The principal component of parenchymal amyloid plaque cores and cerebrovascular amyloid is the amyloid .beta.-protein (A.beta.). It has been shown that this .sup.- 4-kDa protein is produced by various cultured cells including transfected cells stably expressing the amyloid protein precursor (APP), from which A.beta. is derived.
During the past few years, a variety of evidence has emerged indicating that the processing of APP is regulated by signal transduction pathways. Thus, phorbol esters (activators of protein kinase C) and okadaic acid (an inhibitor of protein phosphatases 1 and 2A) increase APP metabolism and secretion. More recently, it has been shown that first messengers known to activate the phospholipase C/protein kinase C cascade increase the secretion of APP. It has also been shown that the formation of a peptide with properties similar to those of A.beta. was decreased by phorbol esters, by okadaic acid, by direct activators of phospholipase C, and by first messengers that activate phospholipase C. However, activation of phospholipase C not only activates protein kinase C (through the formation of diacylglycerol, DAG) but also increases cytoplasmic calcium levels (through the action of inositol triphosphate, IP.sub.3). For this reason, it was important to determine whether the IP.sub.3 /calcium limb of this pathway might, like the DAG/protein kinase C limb, affect APP processing.